CN105188721A - Use of tungsten (VI) salts for the treatment of female infertility in non-diabetic mammals - Google Patents
Use of tungsten (VI) salts for the treatment of female infertility in non-diabetic mammals Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
Abstract
The present invention comprises the use of a therapeutically effective amount of a tungsten (VI) salt with a pharmaceutically or veterinarily acceptable cationic group, or a solvate of said salt, for the preparation of a medicinal product for the treatment of female infertility in non-diabetic mammals.
Description
Technical field
The present invention relates to fertility field.The purposes of female sterile disease is used for the treatment of in particular to tungsten (VI) salt.
Background technology
Infertility may be defined as the disease still cannot become pregnant after conventional, unshielded sexual intercourse in 1 year.Specifically, female sterile disease can relate to and cannot to become pregnant and/or cannot be conceived to mature.
Although estimate to have difficulties in infertility prevalence, it has been generally acknowledged that in a certain stage childbearing age, in every four women, just have one to suffer from infertility.
The main cause of female infertility comprises ovulatory dysfunction, reproductive system pathology, the follicle consumption that Oocyte quality declines and comes with the age increases.But still have the women of significant proportion to suffer from agnogenic infertility, also referred to as fertility, one of its possible cause may relate to the defect in implantation process.
Especially, in the biological reason of many female infertilities, significantly outstanding reason relates to regulation and control follicular development, ovulation, immature egg cell (oocyte) migration and follow-uply to become pregnant and zygote is lacked of proper care in the hormonal stimulation of Uterus wall implantation.This overall process is subject to the hormone secretion regulation and control of specific endocrine organ, such as hypophysis, hypothalamus and thyroid.
Therefore, in the main reason of infertility, significantly outstanding is the ovulatory dysfunction that possible change zygote implantation, such as, lack ovulation, and the related pathologies reason of the anatomy in reproductive system and uterus and functional disorder.
The known Different therapy to female sterile disease, comprises and is used for the treatment of hormone problem and is correlated with the drug products for administration of infertility (such as ovulation failure), and external fertilization and intrauterine insemination technology.
But the obtainable ratio of becoming pregnant of above-mentioned therapy has a definite limitation.Therefore, such as, according to observations, by clomiphene citrate (stilbene class medicine), drug treatment female ovulation is irregular or do not ovulate, and can recover ovulation in high proportion, but probability of becoming pregnant is still low, is equal to or less than 50%.
On the other hand, external fertilization therapy is very effective in the fertilizing oocytes stage.But the rate of transform (embryo is implantation in Uterus wall) is low, carries out multiple embryo's transfer in each IVF cycles thus, cause the excessive risk of multiple pregnancy at high proportion.
Finally, known Metabolic disorder (such as diabetes or obesity) can be limited along with fertility.Known obesity or the diabetic female mice part or all of RI in hyperglycemia, insulinemia and/or body weight brings the raising of fertility.
Different pharmacotherapys, such as metformin or tungsten (VI) salt, or even lifestyle change, be proved and can have improved diabetes or insulin imbalance, such as insulin deficit or insulin resistance, obtain the effect partially or completely recovering reproductive function.For the special case of sodium tungstate, known to the rat of injecting streptozotocin induced insulin shortage and diabetes, under sodium tungstate long-term treatment (10 weeks), because of diabetes partial recovery, part has recovered serum insulin levels.Thus, when above-mentioned female rats and the healthy male rat copulation of diabetes partial recovery, according to observations, except diabetes partial recovery, female rats has also replied part reproductive performance.Especially, according to observations, after sodium tungstate treatment, the female mice of diabetes partial recovery is increased to 66% relative to the fertility percentage ratio of positive dilatation and curettage of uterine number, this percentage ratio is lower than female mice (the 100%) (cf.J.Ballesteret.ai of non-diabetic, " Tungstateadministrationimprovesthesexualandreproductivef unctioninfemaleratswithstreptozotocin-induceddiabetes ", HumanReproduction, 2007, vol.22, pp.2128-2135).
In sum, although the existing close combat of female sterile disease treatment, the invalid patient that thus cannot cure of current therapy is still had.Therefore, still need to explore there is more high-efficiency new therapy to treat female sterile disease.
Summary of the invention
Inventor finds, uses tungsten (VI) salt of the treatment effective dose with the acceptable cation group of pharmacy or veterinary, or its solvate, can be used for the purposes of the medicine for the preparation of the mammiferous female sterile disease for the treatment of non-diabetic.
Although known sodium tungstate can by making normalize blood sugar levels; thus part recovers the reproductive dysfunction of diabetic female mice, but prior art is not recorded or is implied that sodium tungstate self has the female repro ductive system functional activity that can be used for treating female sterile disease.
It should be pointed out that in prior art, sodium tungstate shows the effectiveness to making normalize blood sugar levels.Especially, file EP1400246 discloses the pharmaceutical composition of tungsten (VI) compound, and the blood glucose for reducing 1 type or type 2 diabetes mellitus (IDDM) patient is too high.
It is for not recovering ovulation by change glucose metabolism or body weight and/or improving effective therapy of embedding of ovum that the present inventor illustrates tungsten (VI) salt, thus, the administration of tungsten (VI) salt is the effective therapy being used for the treatment of non-diabetic female mammal infertility.
This aspect can also be formulated as tungsten (VI) salt of the treatment effective dose with the acceptable cation group of pharmacy or veterinary, or its solvate, for the preparation of being used for the treatment of the mammiferous female sterile disease of non-diabetic.It also relates to the method being used for the treatment of the adjoint disease of non-diabetic female mammal infertility or disease, comprise tungsten (VI) salt with the treatment effective dose with the acceptable cation group of pharmacy or veterinary, or its solvate, to the mammal administration needing described treatment.
Hereinafter will describe with tungsten (VI) salt of the treatment effective dose of the acceptable cation group of pharmacy or veterinary or its solvate for the preparation of the preferred specific embodiment of purposes of medicine being used for the treatment of non-diabetic mammiferous female sterile disease, and be used for the treatment of tungsten (VI) salt of the treatment effective dose with the acceptable cation group of pharmacy or veterinary or the preferred specific embodiment of its solvate of non-diabetic mammiferous female sterile disease, and be used for the treatment of the method for the adjoint disease of non-diabetic female mammal infertility or disease.In addition, the present invention also comprises likely combining of preferred specific embodiment described in the application.
" the acceptable cation group of pharmacy or veterinary " alleged by the application refers to and can form treatment effective tungsten (VI) salt and any acceptable non-toxic inorganic or the organic cation that are applicable to pharmacy or veterinary's therapy.
Tungstate anion invariably accompanies cation group, thus forms neutral valerate.In one embodiment of the invention, tungsten (VI) salt is the salt comprising the cation group being selected from alkaline kation or alkaline earth cation.The cation group of described salt is preferably selected from sodium, potassium, magnesium and calcium.Preferably, tungsten (VI) salt is the sodium salt of tungsten (VI).
The present invention also comprise tungsten (VI) salt solvate and for the preparation of the purposes of medicine being used for the treatment of the mammiferous female sterile disease of non-diabetic.In one embodiment of the present of invention, the dihydrate of above-mentioned tungsten (VI) salt during described solvate.
Preferably, the solvate of tungsten (VI) salt is commercially available sodium tungstate dihydrate.
In one embodiment of the present of invention, mammal is the mankind.In a preferred embodiment, tungsten of the present invention (VI) salt can be used for for the preparation of the purposes for the treatment of with the medicine of the female sterile disease of the change of hypothalamic pituitary axis.Disease or the disease of the described change with hypothalamic pituitary axis comprise polycystic ovarian syndrome, metabolism syndrome, hyperprolactinemia, endometriosis, drinking and eating irregularly, obesity, hypothyroidism, multiple sclerosis, rheumatoid arthritis, lupus erythematosus, liver cirrhosis, celiac disease, chronic renal failure and the idiopathic cause of disease etc.
In a preferred embodiment, tungsten of the present invention (VI) salt can be used for the medicine preparing treatment idiopathic female sterile disease.Identical and the commutative use of described " fertility " or " infertility without surperficial reason " concept implication.Described concept refers to the infertility case cannot finding out cause of infertility in standard sterility test.
In a further preferred embodiment, tungsten of the present invention (VI) salt can be used for preparing Therapeutic diet and to lack of proper care the medicine of the female sterile disease caused.Described drinking and eating irregularly, with the change of hypothalamic pituitary axis, comprises anorexia nervosa and disease of eating too much at one meal etc.
The ovum that term " ovulation " is interpreted as women is released into the process in uterus, term " recovers to ovulate " and is interpreted as rebuilding the process of menstrual cycle, namely rebuilds in the women of irregular (oligo-ovulation) of not ovulating (anovulation) or ovulate and regularly discharges the process of ovum to uterus.This means, tungsten of the present invention (VI) salt can be used for preparing treatment and cannot to ovulate (anovulation) or needs improve the medicine of female sterile disease of the women of efficiency (oligo-ovulation) of ovulating.
As display clear in the table 1 of embodiment, the administration of tungsten (VI) salt can in 100% connect in subject non-diabetic female mice and recover the estrus cycle rapidly (treatment after starting only 7 days in).Ovulation has been recovered during the administration of tungsten of the present invention (VI) salt, and the body weight do not changed by treatment female mice or blood glucose (see table 3 and table 4).Therefore, one embodiment of the present of invention relate to use above-mentioned tungsten (VI) salt or its solvate, for the preparation of the purposes of the medicine for the treatment of female sterile disease, comprise and recover ovulation.
On the other hand, display as clear in the experimental result in the table 2 of embodiment, the administration of tungsten (VI) salt can recover to obtain average 5 implantation embryos or birth cub in the non-diabetic mice in normal estrus cycle in the treatment that is subject to of 80%.Therefore, one embodiment of the present of invention relate to use above-mentioned tungsten (VI) salt of the present invention or its solvate, for the preparation of the purposes of the medicine for the treatment of female sterile disease, comprise the zygote implantation improved on Uterus wall.
Term " improves zygote implantation " and is interpreted as improving the process that ovum enters uterus implantation efficiency.This means, tungsten of the present invention (VI) salt can be used for improving the ovum quantity at uterus implantation, or improves success rate of becoming pregnant, and can not improve multiple risk of pregnancy.
One embodiment of the present of invention relate to use above-mentioned tungsten (VI) salt or its solvate, for the preparation of the medicine for the preparation for the treatment of idiopathic female sterile disease, comprise the zygote implantation recovering ovulation and improve Uterus wall.
Therefore, tungsten (VI) salt is used to can be used for by improving pregnancy rate and treat female sterile disease.Therapy of the present invention can be used as ovulating normalization and/or improve the alternative drugs therapy of existing therapy of ovum Uterus wall implantation, or as the association therapy of intrauterine insemination and/or external fertilization technology, to improve the Implantation rate of transition phase.
One embodiment of the present of invention relate to use tungsten (VI) salt or its solvate, and wherein said tungstates is a part for pharmacy or veterinary composition, and described compositions also comprises the acceptable excipient of pharmacy or veterinary or carrier.In one embodiment of the present of invention, described pharmacy or veterinary composition are for oral compositions, especially solid oral composition (such as tablet or capsule) and Liquid oral compositions (such as oral liquid or oral administration mixed suspension).
Term " the acceptable excipient of pharmacy or veterinary or carrier " refers to the excipient or the carrier that are applicable to prepare medical composition in pharmacy or veterinary's technology.Described composition, excipient or carrier, must be compatible with other compositions of compositions.It also must be applicable to contact with the mankind or animal tissue or organ, and without undue toxicity, zest, anaphylaxis or other Immunogenicities or complication, has rational risk/earnings ratio.
Tungsten (VI) salt is for the treatment of obesity or diabetes." treatment effective dose " described in the application refers to tungsten (VI) the salt dosage being enough to the female sterile disease for the treatment of described in the application.Tungsten described in the application (VI) salt given dose is decided by the actual conditions of case, comprise the salt of such as administration, dosage regimen, the pharmacy of administration or veterinary composition, and patient characteristic (comprising height, body weight, age etc.), and the character of disease and sections.Such as, can above-mentioned tungsten (VI) salt use amount can at 50-500mg/kg/ days.
Usually, in rodent, the treatment effective dose being used for the treatment of tungsten (VI) salt of above-mentioned female sterile disease can at 100-350mg/kg/ days.Preferably, this treatment effective dose is at 150-280mg/kg/ days.
In embodiments of the invention, illustrate be used for the treatment of be called IRS-/-animal model in non-diabetic mammal in tungsten (VI) the salt effective dose of female sterile disease.Described female mice is good non-diabetic infertility mouse model.In addition, the good model of this animal model or non-diabetic infertility women.
In the specification and claims, term " comprises " and variant should not be construed as and gets rid of other technologies features, additive, composition or step.In addition, term " comprise " and comprising " consisting of ".To those skilled in the art, should be appreciated that can part from this description and part understands other objects of the present invention, a little and feature from enforcement of the present invention.Following examples, only for illustrations object, do not limit any aspect of the present invention.
Detailed description of the invention
1. animal model (IRS-/-female mice) explanation
IRS2
-/-mouse model is the mouse model (Burkset.a/., " IRS-2pathwaysintegratefemalereproductionandenergyhomeost asis ", Nature.2000, vol.407, pp.377-382) having knocked out Irs2 gene.Irs2 gene elmination translation becomes obvious male and female two type relevant to fertility and carbohydrate metabolism.
Namely the male mice of this model shows insulin resistance and serious hyperglycemia from young.On the contrary, female mice then keeps relative euglycemia, until age (4-5 month) after a while.
IRS2
-/-female mice shows low follicular development and continues not ovulate, along with most of mice without the estrus cycle.
IRS2
-/-the pregnancy rate of female mice is 9%, by comparison, and IRS
wt(IRS-2
+ /+wild type) pregnancy rate of female mice is 100%.
2. ovulation, implantation and research of becoming pregnant
A. laboratory animal
The IRS2 in 10 6-8 age in week
-/-female mice.
" the wild type " (IRS in 6 6-8 age in week
wt) male mice.
Male and female mice is raised in cages respectively under normal operation, namely 12 little time/secretly circulate, and controlled humidity and temperature.Laboratory animal is taken food (being also called free choice feeding) voluntarily with fed standard diet.
B. test method
Pretreatment stage
Adapt to after a period of time, to raise in cages IRS2 with every cage 4-6 mice group
-/-female mice.In pretreatment stage (2 weeks), give animal without wolframic acid drinking water.
Treatment stage
After pretreatment stage (treating the 0th day), with the distilled water solution of 2mg/ml sodium tungstate dihydrate (purchased from CarloErba) the middle administration of drinking water (free choice feeding) 4 weeks, then put to death animal.The sodium tungstate dosage of the every daily digesting of mice is about 180mg/kg body weight.
Copulation
Treatment stage head is after three weeks, by IRS2
-/-female mice continues and IRS
wtmale mice pairing is raised in cages.
Every day observes mice, checks and becomes pregnant or give birth to sign.After 4 weeks, between each cage, exchange male mice, and to be stayed in cage 4 weeks again.
The tungstates administration keeping male mice and female mice jointly to raise in cages 8 weeks.These are after 8 weeks, stop treatment, and male mice and female mice are jointly raised in cages 4 weeks again.
Put to death
After this stage terminates, put to death female mice and carry out slicer, searching for sign of becoming pregnant.
C. experimental result
Ovulation experimental result
During pretreatment stage and treatment during three weeks, within the-8 ,-5 ,-2 ,-1,7,8,14,15,22 day, on random 6 selected female mices, carry out vaginal smear, to determine the Oestrous Stages residing for it.
Introduce 1-2ml saline solution with Pasteur liquid-transfering gun to mouse vagina, gather vaginal discharge with same liquid-transfering gun and be placed on slide.After air-dry, fix with Pasteur (Papanicolaou) technology and dye.
Pasteur's technology comprises the vaginal smear dyeing to being fixed on slide, and step is as follows:
-submergence 10 times in 50%v/v ethanol;
-submergence 3 minutes in Harris hematoxylin solution;
-with tap water;
-the middle submergence of acidic ethanol (1% hydrochloric acid) 10 times;
-with tap water;
-submergence 10 times in 95%v/v ethanol;
-submergence 30 seconds in OG-6 solution;
-submergence 10 times in 96%v/v ethanol;
-submergence 1 minute in eosin solution;
-submergence 10 times in 96%v/v ethanol;
-submergence 10 times in 86%v/v ethanol; And
-submergence 10 times in dimethylbenzene;
By the technician undergone training, mono blind method code is used to analyze goods, to eliminate observer error.
Qualification sample is in which following in stage: dioestrus, proestrum, oestrus, the later stage of oestrusing, anestrus maybe cannot be assessed.These 4 stages circulated with 4-6 days, were the performances normally sending out clear the cycle, and lacking this circulation and continuing to rest on anestrus, dioestrus or proestrum is then the performance that shortage sends out the cycle clear.
In 10 female mices in experiment, table 1 summarizes at described 6 IRS2
-/-what the vaginal smear in female mice drew sends out clear the phase of the cycles.
Table 1
Each stage in estrus cycle is: A-anestrus; D-dioestrus; P-proestrum; E-oestrus; And M-oestruses the later stage.
IRS2 in table 1
-/-oestrous Stages display indicated by female mice vaginal smear, during pretreat, all mices are all in proestrum (P) or dioestrus (D), are not namely in heat.
But, after starting tungstates administration, observe IRS2
-/-female mice is in late period of oestrusing, i.e. oestrus (E) and oestrus the later stage (M), and this is the performance recovering the normal estrus cycle.
The above results shows, the administration of tungsten (IV) salt (can be treated the 7th day) rapidly and be recovered the sterile IRS2 of non-diabetic
-/-the estrus cycle of 100% test mice in mice.
Implantation and experimental result of becoming pregnant
After the copulation of method described in B group terminates period, put to death female mice and also carry out vivisection inspection to find to become pregnant sign.
Summarize the Mus age in treatment period in table 2, whether become pregnant and embryo's number of every female mice.
Table 2
The experimental result of table 2 shows, the pregnancy rate of not treating in IRS2 female mice is 9%, meanwhile, with the IRS2 of tungstates treatment
-/-" pregnancy rate of female mice is increased to 80%.
In addition, the above results also shows, the average cub/implantation embryo quantity of each female mice gestation is about 5, and this quantity can be regarded as and female mice cub similar number.
Therefore, the experimental result of table 1 and table 2 shows, tungsten (IV) salt is the effective therapy for recovering to ovulate and/or improve ovum implantation.Therefore, tungsten (IV) the salt administration described in the present invention has direct effect to female repro ductive system, because of but be used for the treatment of effective therapy of non-diabetic female mammal infertility.
3. blood glucose and body weight research
A. laboratory animal
6 IRS2
-/-female mice, 6-8 week age.
To raise in cages under normal operation female mice, namely 12 little time/secretly circulate, and controlled humidity and temperature.Laboratory animal is taken food (being also called free choice feeding) voluntarily with fed standard diet.
B. experimental technique
Treatment stage
After adapting to a period of time, after pretreatment stage (treating the 0th day), with the distilled water solution of 2mg/ml sodium tungstate dihydrate (purchased from CarloErba) the middle administration of drinking water (free choice feeding) 12 days.
C. experimental result
In the 0th, 2,5,7,9 and 12 day monitoring body weight of treatments period, and fasting is from tail vein haemospasia after 6 hours in the aforementioned date, and use glucose sensor measures blood glucose (RocheAccuTrendGlucoseSensor.Mannheim, Germany).
Table 3 summarizes blood sugar level (unit: mg/dl), and table 4 summarizes the body weight (unit: g) of mice at experimental session.
Table 3
Table 4
The experimental result of Fig. 3 and Fig. 4 shows, during sodium tungstate administration, treatment starts not observe body weight change or change of blood sugar in latter 12 days, and in same period, tested female mice from treatment the 7th day compunction successful reconstitution ovulation (see table 1).
Therefore, the experimental result in table 1-4 shows, tungsten (IV) salt is for not changed by body weight and carbohydrate metabolism change and recover ovulation and/or improve effective therapy of ovum implantation.Therefore, tungsten (IV) the salt administration described in the present invention has direct effect to female repro ductive system, because of but be used for the treatment of effective therapy of non-diabetic female mammal infertility.
Claims (15)
1. treat tungsten (VI) salt or the purposes of its solvate in the medicine for the preparation of the mammiferous female sterile disease for the treatment of non-diabetic of effective dose, wherein said tungsten (VI) salt has the acceptable cation group of pharmacy or veterinary.
2. purposes according to claim 1, is characterized in that, described mammal is the mankind.
3. purposes according to claim 1 and 2, is characterized in that, described cation group is alkaline kation or alkaline earth cation.
4. purposes according to claim 3, is characterized in that, described cation group is selected from: sodium, potassium, magnesium and calcium.
5. purposes according to claim 4, is characterized in that, described tungsten (VI) salt is the sodium salt of tungsten (VI).
6. the purposes according to any one of claim 1-5, is characterized in that, described solvate is dihydrate.
7. the purposes according to any one of claim 1-6, is characterized in that, the treatment of described female sterile disease comprises recovery ovulation.
8. the purposes according to any one of claim 1-7, is characterized in that, the treatment of described female sterile disease comprises the germ cell implantation improved on Uterus wall.
9. the purposes according to any one of claim 1-8, is characterized in that, the generation of described female infertility is with the change of hypothalamic pituitary axis.
10. purposes according to claim 9, is characterized in that, the change of described hypothalamic pituitary axis is selected from: polycystic ovarian syndrome, metabolism syndrome, hyperprolactinemia, endometriosis, drinking and eating irregularly, obesity, hypothyroidism, multiple sclerosis, rheumatoid arthritis, lupus erythematosus, liver cirrhosis, celiac disease, chronic renal failure and the idiopathic cause of disease.
11. purposes according to claim 10, is characterized in that, the change of described hypothalamic pituitary axis is the idiopathic cause of disease.
12. purposes according to claim 10, is characterized in that, described drinking and eating irregularly is selected from anorexia nervosa and disease of eating too much at one meal.
13. purposes according to any one of claim 1-12, it is characterized in that, described tungsten (VI) salt or its solvate are parts for pharmacy or veterinary composition, and described compositions also comprises the acceptable excipient of pharmacy or veterinary or carrier.
14. purposes according to claim 13, is characterized in that, described pharmacy or veterinary composition are for oral compositions.
15. purposes according to claim 14, is characterized in that, described is fluid composition for oral compositions.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ESP201330071 | 2013-01-22 | ||
| ES201330071A ES2478790B1 (en) | 2013-01-22 | 2013-01-22 | Use of tungsten salts (VI) for the treatment of female infertility in non-diabetic mammals |
| PCT/EP2014/051141 WO2014114644A1 (en) | 2013-01-22 | 2014-01-21 | Use of tungsten (vi) salts for the treatment of female infertility in non-diabetic mammals |
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| Publication Number | Publication Date |
|---|---|
| CN105188721A true CN105188721A (en) | 2015-12-23 |
| CN105188721B CN105188721B (en) | 2017-10-31 |
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| CN201480016951.6A Active CN105188721B (en) | 2013-01-22 | 2014-01-21 | Tungsten（VI）Salt is used for the purposes for treating the female sterile disease of non-diabetic mammal |
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|---|---|---|---|---|
| ES2551828B1 (en) * | 2014-05-21 | 2016-09-12 | Oxolife S.L. | Food compositions comprising tungsten salts (VI) |
| ES2639588B1 (en) * | 2014-05-21 | 2018-09-06 | Oxolife, S.L. | Use of a tungsten salt (VI) to promote fertility and normal reproduction in a non-diabetic female mammal |
| AU2014401750B2 (en) * | 2014-07-21 | 2019-10-24 | Oxolife S.L | Tungsten (VI) salts used to treat infertility, for stimulating fertility and normal reproduction in a non-diabetic female mammal, and for improving the effectiveness of assisted reproduction techniques |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4328134A (en) * | 1980-05-06 | 1982-05-04 | Schally Andrew Victor | Anorexigenic peptides |
| WO2004030687A1 (en) * | 2002-10-02 | 2004-04-15 | Yeda Research And Development Co. Ltd. | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
| US20040131697A1 (en) * | 2001-05-16 | 2004-07-08 | Ramon Gomis De Barbara | Oral compositions for the treatment of obese non-diabetic mammals, including humans |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2108642B1 (en) * | 1995-07-26 | 1998-08-16 | Quimica Farm Bayer Sa | TUNGSTEN (VI) COMPOSITIONS FOR THE ORAL TREATMENT OF DIABETES MELLITUS. |
| RU2141361C1 (en) * | 1998-03-12 | 1999-11-20 | Пермская государственная медицинская академия | Method of treatment of anovulatory fertility at obesity |
| RU2270684C1 (en) * | 2005-01-20 | 2006-02-27 | Анатолий Григорьевич Гриценко | Medicinal preparation "vitasorb" |
| JP2009502891A (en) * | 2005-07-29 | 2009-01-29 | ユニベルシダード デ バルセロナ | Pharmaceutical composition comprising tungstate (VI) for the treatment of neurodegenerative diseases, in particular Alzheimer's disease and schizophrenia |
| US20060100154A1 (en) * | 2005-10-13 | 2006-05-11 | Yeda Research And Development Co | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4328134A (en) * | 1980-05-06 | 1982-05-04 | Schally Andrew Victor | Anorexigenic peptides |
| US20040131697A1 (en) * | 2001-05-16 | 2004-07-08 | Ramon Gomis De Barbara | Oral compositions for the treatment of obese non-diabetic mammals, including humans |
| WO2004030687A1 (en) * | 2002-10-02 | 2004-04-15 | Yeda Research And Development Co. Ltd. | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
Non-Patent Citations (4)
| Title |
|---|
| DEBORAH J. BURKS ET AL.: ""IRS-2 pathways integrate female reproduction and energy homeostasis"", 《NATURE》 * |
| J. BALLESTER ET AL.: ""Tungstate administration improves the sexual and reproductive function in female rats with streptozotocin-induced diabetes"", 《HUMAN REPRODUCTION》 * |
| 张海蓉等: ""肥胖对女性生殖系统功能影响的研究进展"", 《山东医药》 * |
| 金利娜: ""肥胖对生殖功能的影响及减重对肥胖无排卵妇女生殖功能的改善"", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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